Publications - 2023
Mobile application-assisted graded exercise practical: a remote teaching strategy to promote motivation and experiential learning in exercise physiology |
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Amanda Huee-Ping Wong, Lik-Wei Wong, and Ivan Cherh Chiet Low
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| Adv Physiol Educ 47: 215–221, 2023. |
| Abstract |
| Practical classes are critical instructional activities in facilitating learning and motivation in health sciences education. With increasing pedagogical activities being conducted in virtual or remote settings, this study assessed how a remote practical assisted by physiological monitoring smartphone applications impacted student motivation and the achievement of intended learning outcomes in exercise physiology teaching. A total of 24 students (out of 30; 80%) were surveyed via a mixed-methods questionnaire containing 27 closed-ended, and 3 the traditional in-class practical in randomized order. Unpaired Student’s t tests were performed for comparisons between interventions with a significance level set at P < 0.05. Students reported that both remote and in-class practicals strongly facilitated the achievement of learning outcomes. Self-reported scores for student satisfaction and perceived achievement of learning outcomes were similar between the two practical methodologies. Student motivation scores assessed using the Lab Motivation Scale revealed that students were more motivated during the remote practical, particularly in the effort domain (P < 0.05). This was in line with the identified themes from the qualitative responses that indicated that the remote practical was more engaging than the in-person practical, with greater opportunities for experiential learning and class involvement being the main factors underlying these findings. Taken together, remote practicals can be critical aspects of a blended learning curriculum that encourages student engagement and experiential learning. With further advancements in physiological monitoring wearables and smartphone technologies, remote practicals can be potential alternatives to traditional in-person practicals in exercise physiology teaching. |
FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| Ling Shuo-Chien |
| iScience, Volume 26, Issue 11, 108152 |
| Abstract |
| MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS. |
Mobile application-assisted graded exercise practical: a remote teaching strategy to promote motivation and experiential learning in exercise physiology |
| Ivan Cherh Chiet Low |
| https://doi.org/10.1152/advan.00231.2022 |
| Abstract |
| "Practical classes are critical instructional activities in facilitating learning and motivation in health sciences education. With increasing pedagogical activities being conducted in virtual or remote settings, this study assessed how a remote practical assisted by physiological monitoring smartphone applications impacted student motivation and the achievement of intended learning outcomes in exercise physiology teaching. A total of 24 students (out of 30; 80%) were surveyed via a mixed-methods questionnaire containing 27 closed-ended, and 3 the traditional in-class practical in randomized order. Unpaired Student’s t tests were performed for comparisons between interventions with a significance level set at P < 0.05. Students reported that both remote and in-class practicals strongly facilitated the achievement of learning outcomes. Self-reported scores for student satisfaction and perceived achievement of learning outcomes were similar between the two practical methodologies. Student motivation scores assessed using the Lab Motivation Scale revealed that students were more motivated during the remote practical, particularly in the effort domain (P < 0.05). This was in line with the identified themes from the qualitative responses that indicated that the remote practical was more engaging than the in-person practical, with greater opportunities for experiential learning and class involvement being the main factors underlying these findings. Taken together, remote practicals can be critical aspects of a blended learning curriculum that encourages student engagement and experiential learning. With further advancements in physiological monitoring wearables and smartphone technologies, remote practicals can be potential alternatives to traditional in-person practicals in exercise physiology teaching. NEW & NOTEWORTHY Remote practical classes, supported by physiological monitoring smartphone applications, were assessed for their utility in facilitating learning and raising student motivation in health sciences education in this study. A comparison of remote practicals with traditional in-class practicals revealed that a remote practical is an effective method for reinforcing physiology learning objectives with the added advantage of increased student motivation. The added value of remote practicals may be attributed to more experiential learning opportunities and increased engagement levels. |
Transcriptional diversity in specific synaptic gene sets discriminates cortical neuronal identity |
| Biol Direct. 2023 May 9;18(1):22. doi: 10.1186/s13062-023-00372-y. |
| Abstract |
| Synapse diversity has been described from different perspectives, ranging from the specific neurotransmitters released, to their diverse biophysical properties and proteome profiles. However, synapse diversity at the transcriptional level has not been systematically identified across all synapse populations in the brain. To quantify and identify specific synaptic features of neuronal cell types we combined the SynGO (Synaptic Gene Ontology) database with single-cell RNA sequencing data of the mouse neocortex. We show that cell types can be discriminated by synaptic genes alone with the same power as all genes. The cell type discriminatory power is not equally distributed across synaptic genes as we could identify functional categories and synaptic compartments with greater cell type specific expression. Synaptic genes, and specific SynGO categories, belonged to three different types of gene modules: gradient expression over all cell types, gradient expression in selected cell types and cell class- or type-specific profiles. This data provides a deeper understanding of synapse diversity in the neocortex and identifies potential markers to selectively identify synapses from specific neuronal populations. |
SIRIUS, Ultra-Scintillating Upconversion Breast Implant for Remote Orthotopic Photodynamic Therapy |
| John Jia En Chua |
| ACS Nano. 2023 Jun 27;17(12):11593-11606. doi: 10.1021/acsnano.3c01916. Epub 2023 Jun 12. |
| Abstract |
| Present day strategies for delivery of wireless photodynamic therapy (PDT) to deep-seated targets are limited by the inadequacy of irradiance and insufficient therapeutic depth. Here we report the design and preclinical validation of a flexible wireless upconversion nanoparticle (UCNP) implant (SIRIUS) that is capable of large field, high intensity illumination for PDT of deep-seated tumors. The implant achieves this by incorporating submicrometer core-shell-shell NaYF4 UCNPs into its design, which significantly enhances upconversion efficiency and mitigates light loss from surface quenching. We demonstrate the efficacy of SIRIUS UCNP implant mediated PDT in preclinical breast cancer disease models. In our in vitro experiments, SIRIUS directed 5-Aminolevulinic Acid (5-ALA) based wireless PDT leads to significant reactive oxygen species (ROS) generation and tumor apoptosis in hormonal receptor+/HER2+ (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. In our in vivo rodent model, SIRIUS-driven PDT is shown to be significant in regressing tumors when applied to orthotopically inoculated breast tumors. Following successful preclinical validation, we also describe a clinical prototype of UCNP breast implant with potential dual cosmetic and onco-therapeutic functions. SIRIUS is an upconversion breast implant for wireless PDT that fulfils all the design prerequisites necessary for seamless clinical translation. |
Magnetic mitohormesis: A non-invasive therapy for inflammatory disorders? |
| ALFREDO FRANCO-OBREGÓN |
| BIOCELL 2023, 47(2), 239-244 |
| Abstract |
| An organism’s survival depends on its ability to adapt to stress. Mitochondria are the cellular integrators of environmental stressors that ultimately translate their responses at the organismal level, and are thus central to the process whereby organisms adapt to their respective environments. Mitochondria produce molecular energy via oxidative phosphorylation that then allows cells to biosynthetically respond and adapt to changes in their environment. Reactive oxygen species (ROS) are by-products of oxidative phosphorylation that can be either beneficial or damaging, depending on the context; ROS are hence both the conveyors of environmental stress as well as cellular “adaptogens”. Mitohormesis refers to the process whereby low levels of oxidative stress spur survival adaptations, whereas excessive levels stymie survival. Low energy and frequency pulsing electromagnetic fields have been recently shown capable of stimulating mitochondrial respiration and ROS production and instilling mitohormetic survival adaptations, similarly to, yet independently of, exercise, opening avenues for the future development of Magnetic Mitohormetic interventions for the improvement of human health. This viewpoint explores the possibilities and nuances of magnetic-based therapies as a form of clinical intervention to non-invasively activate magnetic mitohormesis for the management of chronic diseases. |
Harmonizing Magnetic Mitohormetic Regenerative Strategies: Developmental Implications of a Calcium–Mitochondrial Axis Invoked by Magnetic Field Exposure |
| ALFREDO FRANCO-OBREGÓN |
| Bioengineering 2023, 10(10), 1176; |
| Abstract |
| Mitohormesis is a process whereby mitochondrial stress responses, mediated by reactive oxygen species (ROS), act cumulatively to either instill survival adaptations (low ROS levels) or to produce cell damage (high ROS levels). The mitohormetic nature of extremely low-frequency electromagnetic field (ELF-EMF) exposure thus makes it susceptible to extraneous influences that also impinge on mitochondrial ROS production and contribute to the collective response. Consequently, magnetic stimulation paradigms are prone to experimental variability depending on diverse circumstances. The failure, or inability, to control for these factors has contributed to the existing discrepancies between published reports and in the interpretations made from the results generated therein. Confounding environmental factors include ambient magnetic fields, temperature, the mechanical environment, and the conventional use of aminoglycoside antibiotics. Biological factors include cell type and seeding density as well as the developmental, inflammatory, or senescence statuses of cells that depend on the prior handling of the experimental sample. Technological aspects include magnetic field directionality, uniformity, amplitude, and duration of exposure. All these factors will exhibit manifestations at the level of ROS production that will culminate as a unified cellular response in conjunction with magnetic exposure. Fortunately, many of these factors are under the control of the experimenter. This review will focus on delineating areas requiring technical and biological harmonization to assist in the designing of therapeutic strategies with more clearly defined and better predicted outcomes and to improve the mechanistic interpretation of the generated data, rather than on precise applications. This review will also explore the underlying mechanistic similarities between magnetic field exposure and other forms of biophysical stimuli, such as mechanical stimuli, that mutually induce elevations in intracellular calcium and ROS as a prerequisite for biological outcome. These forms of biophysical stimuli commonly invoke the activity of transient receptor potential cation channel classes, such as TRPC1. |
Concurrent Optical- and Magnetic-Stimulation-Induced Changes on Wound Healing Parameters, Analyzed by Hyperspectral Imaging: An Exploratory Case Series |
| ALFREDO FRANCO-OBREGÓN |
| Bioengineering 2023, 10(7), 750; |
| Abstract |
| The effects of concurrent optical and magnetic stimulation (COMS) therapy on wound-healing-related parameters, such as tissue oxygenation and water index, were analyzed by hyperspectral imaging: an exploratory case series. Background: Oedema and inadequate perfusion have been identified as key factors in delayed wound healing and have been linked to reduced mitochondrial respiration. Targeting mitochondrial dysfunction is a promising approach in the treatment of therapy refractory wounds. This sub-study aimed to investigate the effects of concurrent optical and magnetic stimulation (COMS) on oedema and perfusion through measuring tissue oxygenation and water index, using hyperspectral imaging. Patients and methods: In a multi-center, prospective, comparative clinical trial, eleven patients with chronic leg and foot ulcers were treated with COMS additively to Standard of Care (SOC). Hyperspectral images were collected during patient visits before and after treatment to assess short- and long-term hemodynamic and immunomodulatory effects through changes in tissue oxygenation and water index. Results: The average time for wound onset in the eleven patients analyzed was 183 days, with 64% of them being considered unresponsive to SOC. At week 12, the rate of near-complete and complete wound closure was 64% and 45%, respectively. COMS therapy with SOC resulted in an increased short-term tissue oxygenation over the 8-week treatment phase, with oxygen levels decreasing in-between patient visits. The study further found a decrease in tissue water content after the therapy, with a general accumulation of water levels in-between patient visits. This study’s long-term analysis was hindered by the lack of absolute values in hyperspectral imaging and the dynamic nature of patient parameters during visits, resulting in high interpatient and intervisit variability. Conclusions: This study showed that COMS therapy as an adjunct to SOC had a positive short-term effect on inflammation and tissue oxygenation in chronic wounds of various etiologies. These results further supported the body of evidence for safety and effectiveness of COMS therapy as a treatment option, especially for stagnant wounds that tended to stay in the inflammatory phase and required efficient phase transition towards healing. |
The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective |
| ALFREDO FRANCO-OBREGÓN |
| Bioengineering 2023, 10(8), 956; |
| Abstract |
| Muscle function reflects muscular mitochondrial status, which, in turn, is an adaptive response to physical activity, representing improvements in energy production for de novo biosynthesis or metabolic efficiency. Differences in muscle performance are manifestations of the expression of distinct contractile-protein isoforms and of mitochondrial-energy substrate utilization. Powerful contractures require immediate energy production from carbohydrates outside the mitochondria that exhaust rapidly. Sustained muscle contractions require aerobic energy production from fatty acids by the mitochondria that is slower and produces less force. These two patterns of muscle force generation are broadly classified as glycolytic or oxidative, respectively, and require disparate levels of increased contractile or mitochondrial protein production, respectively, to be effectively executed. Glycolytic muscle, hence, tends towards fibre hypertrophy, whereas oxidative fibres are more disposed towards increased mitochondrial content and efficiency, rather than hypertrophy. Although developmentally predetermined muscle classes exist, a degree of functional plasticity persists across all muscles post-birth that can be modulated by exercise and generally results in an increase in the oxidative character of muscle. Oxidative muscle is most strongly correlated with organismal metabolic balance and longevity because of the propensity of oxidative muscle for fatty-acid oxidation and associated anti-inflammatory ramifications which occur at the expense of glycolytic-muscle development and hypertrophy. This muscle-class size disparity is often at odds with common expectations that muscle mass should scale positively with improved health and longevity. Brief magnetic-field activation of the muscle mitochondrial pool has been shown to recapitulate key aspects of the oxidative-muscle phenotype with similar metabolic hallmarks. This review discusses the common genetic cascades invoked by endurance exercise and magnetic-field therapy and the potential physiological differences with regards to human health and longevity. Future human studies examining the physiological consequences of magnetic-field therapy are warranted. |
Transcriptional diversity in specific synaptic gene sets discriminates cortical neuronal identity |
| Authors |
| Biol Direct. 2023 May 9;18(1):22. doi: 10.1186/s13062-023-00372-y. |
| Abstract |
| Synapse diversity has been described from different perspectives, ranging from the specific neurotransmitters released, to their diverse biophysical properties and proteome profiles. However, synapse diversity at the transcriptional level has not been systematically identified across all synapse populations in the brain. To quantify and identify specific synaptic features of neuronal cell types we combined the SynGO (Synaptic Gene Ontology) database with single-cell RNA sequencing data of the mouse neocortex. We show that cell types can be discriminated by synaptic genes alone with the same power as all genes. The cell type discriminatory power is not equally distributed across synaptic genes as we could identify functional categories and synaptic compartments with greater cell type specific expression. Synaptic genes, and specific SynGO categories, belonged to three different types of gene modules: gradient expression over all cell types, gradient expression in selected cell types and cell class- or type-specific profiles. This data provides a deeper understanding of synapse diversity in the neocortex and identifies potential markers to selectively identify synapses from specific neuronal populations. |
Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD |
| Shazib Pervaiz |
| Biology (Basel). 2023 Apr 25;12(5):647. doi: 10.3390/biology12050647. |
| Abstract |
| Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy. |
CAMK2D serves as a molecular scaffold for RNF8-MAD2 complex to induce mitotic checkpoint in glioma |
| Derrick Sek Tong Ong, Karen Crasta |
| Cell Death Differ. 2023 Aug;30(8):1973-1987. doi: 10.1038/s41418-023-01192-3. |
| Abstract |
| MAD2 is a spindle assembly checkpoint protein that participates in the formation of mitotic checkpoint complex, which blocks mitotic progression. RNF8, an established DNA damage response protein, has been implicated in mitotic checkpoint regulation but its exact role remains poorly understood. Here, RNF8 proximity proteomics uncovered a role of RNF8-MAD2 in generating the mitotic checkpoint signal. Specifically, RNF8 competes with a small pool of p31comet for binding to the closed conformer of MAD2 via its RING domain, while CAMK2D serves as a molecular scaffold to concentrate the RNF8-MAD2 complex via transient/weak interactions between its p-Thr287 and RNF8's FHA domain. Accordingly, RNF8 overexpression impairs glioma stem cell (GSC) mitotic progression in a FHA- and RING-dependent manner. Importantly, low RNF8 expression correlates with inferior glioma outcome and RNF8 overexpression impedes GSC tumorigenicity. Last, we identify PLK1 inhibitor that mimics RNF8 overexpression using a chemical biology approach, and demonstrate a PLK1/HSP90 inhibitor combination that synergistically reduces GSC proliferation and stemness. Thus, our study has unveiled a previously unrecognized CAMK2D-RNF8-MAD2 complex in regulating mitotic checkpoint with relevance to gliomas, which is therapeutically targetable. |
Apoptotic cell death in disease-Current understanding of the NCCD 2023 |
| Shazib Pervaiz |
| Cell Death Differ. 2023 May;30(5):1097-1154. doi: 10.1038/s41418-023-01153-w. |
| Abstract |
| Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease. |
The effects of low and normal dose ice slurry ingestion on endurance capacity and intestinal epithelial injury in the heat |
| Jason K.W. Lee, Ivan C.C. Low |
| https://doi.org/10.1016/j.jsams.2023.04.008 |
| Abstract |
Effect of ice slurry ingestion on thermoregulatory responses during fixed-intensity cycling in humid and dry heat |
| Jason Kai Wei Lee |
| Eur J Appl Physiol 123, 2225–2237 (2023). |
| Abstract |
Lessons from the Singapore cohorts showcase symposium—open call for collaborations |
| Jason K.W. Leea, Ivan C.C. Low |
| Eur J Epidemiol 38, 713–715 (2023). |
| Abstract |
| European Journal of Epidemiology, published for the first time in 1985, serves as a forum on epidemiology in the broadest sense. It is a peer-reviewed journal dedicated to all fields of epidemiologic research and to epidemiologic and statistical methods. EJE promotes communication among those engaged in research, teaching and application of epidemiology, including those who practice clinical or community medicine. The Journal encourages contributions from a wide variety of fields, including public health, preventive medicine, clinical medicine, health economics, and computational biology and data science applied to health and disease. EJE publishes empirical research findings, methodological developments and opinion articles from as broad a geographical origin as possible, with some focus, but certainly not exclusive, on European topics of relevance for epidemiology. |
Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment |
| Lina H. K. Lim |
| Front. Immunol., 28 June 2023 Sec. Cytokines and Soluble Mediators in Immunity Volume 14 - 2023 |
| Abstract |
| Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1β production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1β enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer. |
Activation of eIF4E-binding-protein-1 rescues mTORC1-induced sarcopenia by expanding lysosomal degradation capacity. |
| Tsai Shih-Yin |
| J Cachexia Sarcopenia Muscle. 2023 Feb;14(1):198-213. doi: 10.1002/jcsm.13121. |
| Abstract |
Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma |
| Reshma Taneja, Derrick Ong |
| J Pathol. 2023 Mar;259(3):342-356. doi: 10.1002/path.6048. |
| Abstract |
| The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. |
Optical Properties and Interference Effects of the Lens Mitochondrion |
| Zakaria Almsherqi |
| Membranes (Basel),2023 Jun 20;13(6):610. doi: 10.3390/membranes13060610. |
| Abstract |
| The lens mitochondrion of the tree shrew, located along the optical pathway between the lens and photoreceptors, has been investigated. The results suggest that the lens mitochondrion acts as a quasi-bandgap or imperfect photonic crystal. Interference effects cause a shift in the focus and introduce wavelength-dependent behavior similar to dispersion. Optical channels within the mitochondrion form a mild waveguide, preferentially propagating light within certain compartments. The lens mitochondrion also functions as an imperfect UV-shielding interference filter. Overall, this study provides insights into the dual role of the lens mitochondrion and the complex behavior of light within biological systems. |
Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST |
| Lina H. K. Lim |
| Nat Commun 2023 Mar 1;14(1):1155. doi: 10.1038/s41467-023-36796-3. |
| Abstract |
| Spatial transcriptomics technologies generate gene expression profiles with spatial context, requiring spatially informed analysis tools for three key tasks, spatial clustering, multisample integration, and cell-type deconvolution. We present GraphST, a graph self-supervised contrastive learning method that fully exploits spatial transcriptomics data to outperform existing methods. It combines graph neural networks with self-supervised contrastive learning to learn informative and discriminative spot representations by minimizing the embedding distance between spatially adjacent spots and vice versa. We demonstrated GraphST on multiple tissue types and technology platforms. GraphST achieved 10% higher clustering accuracy and better delineated fine-grained tissue structures in brain and embryo tissues. GraphST is also the only method that can jointly analyze multiple tissue slices in vertical or horizontal integration while correcting batch effects. Lastly, GraphST demonstrated superior cell-type deconvolution to capture spatial niches like lymph node germinal centers and exhausted tumor infiltrating T cells in breast tumor tissue. |
The effects of low and normal dose ice slurry ingestion on endurance capacity and intestinal epithelial injury in the heat |
| Jason K.W. Leea, Ivan C.C. Low |
| Open AccessPublished:April 29, 2023DOI |
| Abstract |
Effects of Medications on Heat Loss Capacity in Chronic Disease Patients: Health Implications Amidst Global Warming |
| Jason Kai Wei Lee |
| Pharmacological Reviews November 2023, 75 (6) 1140-1166 |
| Abstract |
Stochastic Exceptional Points for Noise-Assisted Sensing |
| Jason Kai Wei Lee |
| Phys. Rev. Lett. 130, 227201 |
| Abstract |
| Noise is a fundamental challenge for sensors deployed in daily environments for ambient sensing, health monitoring, and wireless networking. Current strategies for noise mitigation rely primarily on reducing or removing noise. Here, we introduce stochastic exceptional points and show the utility to reverse the detrimental effect of noise. The stochastic process theory illustrates that the stochastic exceptional points manifest as fluctuating sensory thresholds that give rise to stochastic resonance, a counterintuitive phenomenon in which the added noise increases the system’s ability to detect weak signals. Demonstrations using a wearable wireless sensor show that the stochastic exceptional points lead to more accurate tracking of a person’s vital signs during exercise. Our results may lead to a distinct class of sensors that overcome and are enhanced by ambient noise for applications ranging from healthcare to the internet of things. |
A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence |
| Shazib Pervaiz |
| Redox Biol. 2023 Aug:64:102757. doi: 10.1016/j.redox.2023.102757. |
| Abstract |
| Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we show the existence of a redox state associated with replication stress-induced senescence termed senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe CM-H2DCFDA. Measurement of GSH and GSSH also reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Moreover, supporting the role of superoxide (O2.-) in the SA-redox state, we show that incubation of senescent RPE1-hTERT cells with the O2.- scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidants' reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. SA-redox state does not participate in the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-β-Gal activity. However, SA-redox state is associated with the activation of NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases TFEB protein level, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and influences senescent cells response to senolysis. Furthermore, we provide evidence for crosstalk between SA redox state, p53 and p21. While p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis. |
Brief, weekly magnetic muscle therapy improves mobility and lean body mass in older adults: a Southeast Asia community case study |
| ALFREDO FRANCO-OBREGÓN |
| Paper Volume 15, Issue 6 pp 1768—1790 |
| Abstract |
| Brief (10 min) weekly exposure to low energy pulsed electromagnetic fields (PEMFs) has been shown to improve human muscle mitochondrial bioenergetics and attenuate systemic lipotoxicity following anterior cruciate ligament surgical reconstruction. Here we present data generated from 101 participants, 62% female, aged 38–91 years, recruited from the QuantumTx Demo Centre in Singapore, wherein 87% of participants (n = 88) presented with pre-existing mobility dysfunction and 13% (n = 13) were healthy volunteers. Participants were recruited if: (i) not pregnant; (ii) above 35 years of age and; (iii) without surgical implants. All participants completed mobility testing, pre- and post- PEMF intervention for 12 weeks, whereas bioelectrical impedance analysis was conducted in a subgroup of 42 and 33 participants at weeks 4 and 8, respectively. Weekly PEMF exposure was associated with significant improvements in mobility (Timed Up and Go, 5 times Sit-to-Stand, and 4m Normal Gait Speed) and body composition (increased skeletal muscle mass and reduced total and visceral fat mass), particularly in the older participants. Perception of pain was also significantly reduced. PEMF therapy may provide a manner to counteract age-associated mobility and metabolic disruptions and merits future investigation in randomized controlled trials to elucidate its clinical benefits in the frail and older adult populations. |
HEBP1 - An early trigger for neuronal cell death and circuit dysfunction in Alzheimer's disease |
| John Jia En Chua |
| Semin Cell Dev Biol. 2023 Apr:139:102-110. doi: 10.1016/j.semcdb.2022.07.005. Epub 2022 Jul 14. |
| Abstract |
| Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that gradually impairs memory, cognition and the ability to perform simple daily tasks. It is the most prevalent form of dementia in the elderly and its incidence increases exponentially with age. Neuronal and synapse loss, key hallmarks of the disorder, are widely regarded to occur early during the onset of AD, and the extent of this loss closely correlates with the progression of cognitive decline and dysfunction of the underlying neuronal circuity. Nevertheless, the mechanisms driving neuronal and synapse loss during early AD remains poorly understood. This review focuses on Heme-binding protein 1 (HEBP1), a mitochondrial-associated protein that has recently emerged as an important mediator of neuronal cell death during early AD pathogenesis. Acting downstream of Aβ and heme, HEBP1-mediated apoptosis contributes to neuronal loss and neuronal circuit dysfunction. Deleting HEBP1 expression in neurons protects them from heme- and Aβ-induced apoptosis, both of which are mechanisms implicated in neurodegeneration. HEBP1 participates in heme metabolism and binds to heme to modulate mitochondrial dynamics vital to the maintenance of neural circuitry that is affected in AD. HEBP1 elevation is also associated with AGE/RAGE-related neuronal damage, further implicating its involvement in neuronal loss during early AD. Moreover, F2L, a cleavage product of HEBP1 modulates inflammation. Collectively, these findings highlight the importance of HEBP1 in the disruption of neural circuits during early AD. |